Synergistic antitumor effect of the anti-ErbB2 antibodies trastuzumab and H2-18 on trastuzumab-resistant gastric cancer cells.
Synergistic antitumor effect of the anti-ErbB2 antibodies trastuzumab and H2-18 on trastuzumab-resistant gastric cancer cells.
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DOI：
10.3892/ol.2021.12661
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发表时间：
2021-05
期刊：
影响因子：
2.9
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Wang C;Wang L;Liang B;Zhou B;Sun Y;Meng Y;Dong J;Chen L;Li B
曲妥珠单抗耐药是治疗ErbB 2扩增癌症的严重问题。尽管曲妥珠单抗联合帕妥珠单抗能够部分克服ErbB 2过表达癌症中的曲妥珠单抗耐药性，但其抗肿瘤疗效仍然有限。本研究探讨了曲妥珠单抗与靶向ErbB 2结构域I的抗体H2-18的组合的抗肿瘤活性。细胞增殖和抑制实验表明，H2-18和曲妥珠单抗协同抑制曲妥珠单抗敏感的胃癌细胞系NCI-N87和曲妥珠单抗耐药的胃癌细胞系NCI-N87-TraRT的增殖。此外，在体外和体内，H2-18加曲妥珠单抗比曲妥珠单抗加帕妥珠单抗更有效地抑制NCI-N87-TraRT细胞的生长。与曲妥珠单抗联合帕妥珠单抗相比，H2-18联合曲妥珠单抗对NCI-N87-TraRT细胞集落形成有较强的抑制作用。值得注意的是，H2-18加曲妥珠单抗在诱导细胞死亡方面比曲妥珠单抗加帕妥珠单抗更有效。体内研究表明，H2-18加曲妥珠单抗有效抑制NCI-N87和NCI-N87-TraRT异种移植肿瘤的生长。进一步的实验显示，在NCI-N87-TraRT细胞中，H2-18加曲妥珠单抗在抑制磷酸化（p-）HER 3、p-AKT和p-ERK方面与曲妥珠单抗加帕妥珠单抗相当。然而，与曲妥珠单抗+帕妥珠单抗相比，H2-18+曲妥珠单抗有效地激活了NCI-N87-TraRT细胞中ROS的产生以及JNK和c-jun的磷酸化。因此，H2-18加曲妥珠单抗的抗肿瘤疗效优于曲妥珠单抗加帕妥珠单抗的上级可能主要归因于强效细胞死亡诱导活性。此外，进一步研究了H2-18、曲妥珠单抗和帕妥珠单抗联合用药的体外和体内抗肿瘤作用。结果显示，在所有测试的抗ErbB 2单克隆抗体组合中，H2-18加曲妥珠单抗加帕妥珠单抗显示出最大的抗肿瘤作用。总之，H2-18联合曲妥珠单抗可能是克服ErbB 2扩增胃癌细胞系对曲妥珠单抗耐药的有效策略。
Trastuzumab resistance is a severe problem in the treatment of ErbB2-amplified cancer. Although trastuzumab plus pertuzumab is able to partly overcome trastuzumab resistance in ErbB2-overexpressing cancer, its antitumor efficacy remains limited. The present study investigated the antitumor activity of the combination of trastuzumab with H2-18, which is an antibody targetinsg ErbB2 domain I. Cell proliferation and inhibition experiments indicated that H2-18 and trastuzumab synergistically inhibited the proliferation of both the trastuzumab-sensitive gastric cancer cell line, NCI-N87 and the trastuzumab-resistant gastric cancer cell line, NCI-N87-TraRT. Furthermore, H2-18 plus trastuzumab inhibited the growth of NCI-N87-TraRT cells more effectively than trastuzumab plus pertuzumab, both in vitro and in vivo. Compared with trastuzumab plus pertuzumab, H2-18 plus trastuzumab had a potent ability to inhibit NCI-N87-TraRT cells to form colonies. Notably, H2-18 plus trastuzumab was more effective in inducing cell death than trastuzumab plus pertuzumab. The in vivo studies demonstrated that H2-18 plus trastuzumab effectively inhibited the growth of both NCI-N87 and NCI-N87-TraRT xenograft tumors. Further experiments revealed that in NCI-N87-TraRT cells, H2-18 plus trastuzumab was comparable to trastuzumab plus pertuzumab in the inhibition of phosphorylated (p-)HER3, p-AKT and p-ERK. However, compared with trastuzumab plus pertuzumab, H2-18 plus trastuzumab effectively activated ROS production and the phosphorylation of JNK and c-jun in NCI-N87-TraRT cells. Therefore, the superior antitumor efficacy of H2-18 plus trastuzumab over trastuzumab plus pertuzumab may be mainly attributable to the potent cell death-inducing activity. In addition, the in vitro and in vivo antitumor effect of the combination of H2-18, trastuzumab and pertuzumab were further investigated. The results revealed that H2-18 plus trastuzumab plus pertuzumab exhibited a maximal antitumor effect among all the anti-ErbB2 monoclonal antibody combinations tested. In summary, H2-18 plus trastuzumab may have potential as an effective strategy to overcome the resistance to trastuzumab in ErbB2-amplified gastric cancer cell lines.
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影响因子：
4.6
作者：
Stanley A;Ashrafi GH;Seddon AM;Modjtahedi H
通讯作者：
Modjtahedi H
影响因子：
50.3
作者：
Agus, DB;Akita, RW;Sliwkowski, MX
通讯作者：
Sliwkowski, MX
影响因子：
50.3
作者：
Junttila, Teemu T.;Akita, Robert W.;Sliwkowski, Mark X.
通讯作者：
Sliwkowski, Mark X.
抗 ErbB2 全人源抗体可规避曲妥珠单抗耐药性
影响因子：
--
作者：
Lu Q;Wang L;Zhang Y;Yu X;Wang C;Wang H;Yang Y;Chong X;Xia T;Meng Y;Wang Y;Lu C;Zhou L;Li B
通讯作者：
Li B
影响因子：
11.2
作者：
Nahta, R;Hung, MC;Esteva, FJ
通讯作者：
Esteva, FJ